PMID- 30916672
OWN - NLM
STAT- MEDLINE
DCOM- 20190729
LR  - 20190729
IS  - 2040-3372 (Electronic)
IS  - 2040-3364 (Linking)
VI  - 11
IP  - 14
DP  - 2019 Apr 4
TI  - Extracellular vesicles induce minimal hepatotoxicity and immunogenicity.
PG  - 6990-7001
LID - 10.1039/c8nr08720b [doi]
AB  - Extracellular vesicles (EVs) mediate cellular communication through the transfer 
      of active biomolecules, raising interest in using them as biological delivery 
      vehicles for therapeutic drugs. For drug delivery applications, it is important 
      to understand the intrinsic safety and toxicity liabilities of EVs. 
      Nanoparticles, including EVs, typically demonstrate significant accumulation in 
      the liver after systemic administration in vivo. We confirmed uptake of EVs 
      derived from Expi293F cells into HepG2 cells and did not detect any signs of 
      hepatotoxicity measured by cell viability, functional secretion of albumin, 
      plasma membrane integrity, and mitochondrial and lysosomal activity even at high 
      exposures of up to 5 x 1010 EVs per mL. Whole genome transcriptome analysis was 
      used to measure potential effects on the gene expression in the recipient HepG2 
      cells at 24 h following exposure to EVs. Only 0.6% of all genes were found to be 
      differentially expressed displaying less than 2-fold expression change, with 
      genes related to inflammation or toxicity being unaffected. EVs did not trigger 
      any proinflammatory cytokine response in HepG2 cells. However, minor changes were 
      noted in human blood for interleukin (IL)-8, IL-6, and monocyte chemotactic 
      protein 1 (MCP-1). Administration of 5 x 1010 Expi293F-derived EVs to BALB/c mice 
      did not result in any histopathological changes or increases of liver 
      transaminases or cytokine levels, apart from a modest increase in keratinocyte 
      chemoattractant (KC). The absence of any significant toxicity associated with EVs 
      in vitro and in vivo supports the prospective use of EVs for therapeutic 
      applications and for drug delivery.
FAU - Saleh, Amer F
AU  - Saleh AF
AD  - Drug Safety and Metabolism, IMED Biotech unit, AstraZeneca, Cambridge, UK. 
      Amer.saleh@astrazeneca.com.
FAU - Lazaro-Ibanez, Elisa
AU  - Lazaro-Ibanez E
FAU - Forsgard, Malin A-M
AU  - Forsgard MA
FAU - Shatnyeva, Olga
AU  - Shatnyeva O
FAU - Osteikoetxea, Xabier
AU  - Osteikoetxea X
FAU - Karlsson, Fredrik
AU  - Karlsson F
FAU - Heath, Nikki
AU  - Heath N
FAU - Ingelsten, Madeleine
AU  - Ingelsten M
FAU - Rose, Jonathan
AU  - Rose J
FAU - Harris, Jayne
AU  - Harris J
FAU - Mairesse, Maelle
AU  - Mairesse M
FAU - Bates, Stephanie M
AU  - Bates SM
FAU - Clausen, Maryam
AU  - Clausen M
FAU - Etal, Damla
AU  - Etal D
FAU - Leonard, Emilyanne
AU  - Leonard E
FAU - Fellows, Mick D
AU  - Fellows MD
FAU - Dekker, Niek
AU  - Dekker N
FAU - Edmunds, Nicholas
AU  - Edmunds N
LA  - eng
PT  - Journal Article
PL  - England
TA  - Nanoscale
JT  - Nanoscale
JID - 101525249
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Serum Albumin)
RN  - EC 2.6.1.- (Transaminases)
MH  - Animals
MH  - Cytokines/metabolism
MH  - Extracellular Vesicles/*physiology/transplantation
MH  - HEK293 Cells
MH  - Hep G2 Cells
MH  - Humans
MH  - Inflammation Mediators/metabolism
MH  - Liver/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Nanoparticles/chemistry
MH  - Serum Albumin/metabolism
MH  - Transaminases/metabolism
MH  - Transcriptome
EDAT- 2019/03/28 06:00
MHDA- 2019/07/30 06:00
CRDT- 2019/03/28 06:00
PHST- 2019/03/28 06:00 [pubmed]
PHST- 2019/07/30 06:00 [medline]
PHST- 2019/03/28 06:00 [entrez]
AID - 10.1039/c8nr08720b [doi]
PST - ppublish
SO  - Nanoscale. 2019 Apr 4;11(14):6990-7001. doi: 10.1039/c8nr08720b.